Brivudine

Last updated
Brivudine
Brivudine - Brivudin.svg
Clinical data
Trade names Zostex, Mevir, Brivir, many others
Other namesBVDU
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • Contraindicated
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 30%
Protein binding >95%
Metabolism Thymidine phosphorylase
Metabolites Bromovinyluracil
Elimination half-life 16 hours
Excretion 65% renal (mainly metabolites), 20% faeces
Identifiers
  • 5-[(E)-2-bromoethenyl]-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,3,4-tetrahydropyrimidine-2,4-dione
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C11H13BrN2O5
Molar mass 333.138 g·mol−1
3D model (JSmol)
Specific rotation +9°±1°
Density 1.86 g/cm3
Melting point 165 to 166 °C (329 to 331 °F) (decomposes)
  • Br[C@H]=CC=1C(=O)NC(=O)N(C=1)[C@@H]2O[C@@H]([C@@H](O)C2)CO
  • InChI=1S/C11H13BrN2O5/c12-2-1-6-4-14(11(18)13-10(6)17)9-3-7(16)8(5-15)19-9/h1-2,4,7-9,15-16H,3,5H2,(H,13,17,18)/b2-1+/t7-,8+,9+/m0/s1 Yes check.svgY
  • Key:ODZBBRURCPAEIQ-PIXDULNESA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Brivudine (trade names Zostex, Mevir, Brivir, among others) is an antiviral drug used in the treatment of herpes zoster ("shingles"). Like other antivirals, it acts by inhibiting replication of the target virus.

Contents

Medical uses

Brivudine is used for the treatment of herpes zoster in adult patients. It is taken orally once daily, in contrast to aciclovir, valaciclovir and other antivirals. [1] A study has found that it is more effective than aciclovir, but this has been disputed because of a possible conflict of interest on part of the study authors. [2]

Contraindications

The drug is contraindicated in patients undergoing immunosuppression (for example because of an organ transplant) or cancer therapy, especially with fluorouracil (5-FU) and chemically related (pro)drugs such as capecitabine and tegafur, as well as the antimycotic drug flucytosine, which is also related to 5-FU. It has not been proven to be safe in children and pregnant or breastfeeding women. [1]

Adverse effects

The drug is generally well tolerated. The only common side effect is nausea (in 2% of patients). Less common side effects (<1%) include headache, increased or lowered blood cell counts (granulocytopenia, anaemia, lymphocytosis, monocytosis), increased liver enzymes, and allergic reactions. [1]

Interactions

Brivudine interacts strongly and in rare cases lethally with the anticancer drug fluorouracil (5-FU), its prodrugs and related substances. Even topically applied 5-FU can be dangerous in combination with brivudine. This is caused by the main metabolite, bromovinyluracil (BVU), irreversibly inhibiting the enzyme dihydropyrimidine dehydrogenase (DPD) which is necessary for inactivating 5-FU. After a standard brivudine therapy, DPD function can be compromised for up to 18 days. This interaction is shared with the closely related drug sorivudine which also has BVU as its main metabolite. [1] [3]

There are no other relevant interactions. Brivudine does not significantly influence the cytochrome P450 enzymes in the liver. [1]

Pharmacology

Spectrum of activity

The drug inhibits replication of varicella zoster virus (VZV) – which causes herpes zoster – and herpes simplex virus type 1 (HSV-1), but not HSV-2 which typically causes genital herpes. In vitro , inhibitory concentrations against VZV are 200- to 1000-fold lower than those of aciclovir and penciclovir, theoretically indicating a much higher potency of brivudine. Clinically relevant VZV strains are particularly sensitive. [4]

Mechanism of action

Brivudine is an analogue of the nucleoside thymidine. The active compound is brivudine 5'-triphosphate, which is formed in subsequent phosphorylations by viral (but not human) thymidine kinase and presumably by nucleoside-diphosphate kinase. Brivudine 5'-triphosphate works because it is incorporated into the viral DNA, but then blocks the action of DNA polymerases, thus inhibiting viral replication. [1] [4]

Pharmacokinetics

Brivudine is well and rapidly absorbed from the gut and undergoes first-pass metabolism in the liver, where the enzyme thymidine phosphorylase [5] quickly splits off the sugar component, leading to a bioavailability of 30%. The resulting metabolite is bromovinyluracil (BVU), which does not have antiviral activity. BVU is also the only metabolite that can be detected in the blood plasma. [1] [6]

Highest blood plasma concentrations are reached after one hour. Brivudine is almost completely (>95%) bound to plasma proteins. Terminal half-life is 16 hours; 65% of the substance are found in the urine and 20% in the faeces, mainly in form of an acetic acid derivative (which is not detectable in the plasma), but also other water-soluble metabolites, which are urea derivatives. Less than 1% is excreted in form of the original compound. [1]

Chemistry

The molecule has three chiral carbon atoms in the deoxyribose (sugar) part all of which have defined orientation; i.e. the drug is stereochemically pure. [1] The substance is a white powder.

Manufacturing

Main supplier is Berlin Chemie, now part of Italy's Menarini Group. In Central America is provided by Menarini Centro America and Wyeth.[ citation needed ]

History

The substance was first synthesized by scientists at the University of Birmingham in the UK in 1976. It was shown to be a potent inhibitor of HSV-1 and VZV by Erik De Clercq at the Rega Institute for Medical Research in Belgium in 1979. In the 1980s the drug became commercially available in East Germany, where it was marketed as Helpin by a pharmaceutical company called Berlin-Chemie. Only after the indication was changed to the treatment of herpes zoster in 2001 did it become more widely available in Europe. [7] [8]

Brivudine is approved for use in a number of European countries including Austria, Belgium, Germany, Greece, Italy, Portugal, Spain and Switzerland. [9]

Etymology

The name brivudine derives from the chemical nomenclature bromo-vinyl-deoxyuridine or BVDU for short. It is sold under trade names such as Bridic, Brival, Brivex, Brivir, Brivirac, Brivox, Brivuzost, Zerpex, Zonavir, Zostex, and Zovudex. [9]

Research

A Cochrane Systematic Review examined the effectiveness of multiple antiviral drugs in the treatment of herpes simplex virus epithelial keratitis. Brivudine was found to be significantly more effective than idoxuridine in increasing the number of successfully healed eyes of participants. [10]

See also

Related antiviral drugs

Vaccines and other treatments

Related Research Articles

<span class="mw-page-title-main">Varicella zoster virus</span> Herpes virus that causes chickenpox and shingles

Varicella-zoster virus (VZV), also known as human herpesvirus 3 or Human alphaherpesvirus 3 (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting children and young adults, and shingles in adults but rarely in children. VZV infections are species-specific to humans. The virus can survive in external environments for a few hours.

<span class="mw-page-title-main">Shingles</span> Viral disease caused by the varicella zoster virus

Shingles, also known as zoster or herpes zoster, is a viral disease characterized by a painful skin rash with blisters in a localized area. Typically the rash occurs in a single, wide mark either on the left or right side of the body or face. Two to four days before the rash occurs there may be tingling or local pain in the area. Otherwise, there are typically few symptoms though some people may have fever or headache, or feel tired. The rash usually heals within two to four weeks; however, some people develop ongoing nerve pain which can last for months or years, a condition called postherpetic neuralgia (PHN). In those with poor immune function the rash may occur widely. If the rash involves the eye, vision loss may occur.

<span class="mw-page-title-main">Aciclovir</span> Antiviral medication used against herpes, chickenpox and shingles

Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following transplant and severe complications of Epstein–Barr virus infection. It can be taken by mouth, applied as a cream, or injected.

<span class="mw-page-title-main">Valaciclovir</span> Anti-herpes virus drug

Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles). It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. It is taken by mouth.

<span class="mw-page-title-main">Thymidine kinase</span> Enzyme found in most living cells

Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases. Thymidine kinase catalyzes the reaction:

<span class="mw-page-title-main">Vidarabine</span> Chemical compound

Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses.

<span class="mw-page-title-main">Ganciclovir</span> Chemical compound

Ganciclovir, sold under the brand name Cytovene among others, is an antiviral medication used to treat cytomegalovirus (CMV) infections.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar, and a phosphate group with one to three phosphates.

<span class="mw-page-title-main">Idoxuridine</span> Chemical compound

Idoxuridine is an anti-herpesvirus antiviral drug.

<span class="mw-page-title-main">Trifluridine</span> Chemical compound

Trifluridine is an anti-herpesvirus antiviral drug, used primarily on the eye. It was sold under the trade name Viroptic by Glaxo Wellcome, now merged into GlaxoSmithKline. The brand is now owned by Monarch Pharmaceuticals, which is wholly owned by King Pharmaceuticals.

<span class="mw-page-title-main">Sorivudine</span>

Sorivudine (INN), is a nucleoside analogue antiviral drug, marketed under trade names such as Usevir and Brovavir (BMS). It is used for the treatment of varicella zoster virus infections.

<span class="mw-page-title-main">Chickenpox</span> Human viral disease

Chickenpox, also known as varicella, is a highly contagious disease caused by the initial infection with varicella zoster virus (VZV). The disease results in a characteristic skin rash that forms small, itchy blisters, which eventually scab over. It usually starts on the chest, back, and face. It then spreads to the rest of the body. The rash and other symptoms, such as fever, tiredness, and headaches, usually last five to seven days. Complications may occasionally include pneumonia, inflammation of the brain, and bacterial skin infections. The disease is usually more severe in adults than in children.

<span class="mw-page-title-main">Thymidine kinase from herpesvirus</span>

Thymidine kinase from herpesvirus is a sub-family of thymidine kinases.

<span class="mw-page-title-main">Herpes simplex</span> Viral disease caused by herpes simplex viruses

Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected.

<span class="mw-page-title-main">Herpes labialis</span> Herpes simplex virus infection of the lip

Herpes labialis, commonly known as cold sores or fever blisters, is a type of infection by the herpes simplex virus that affects primarily the lip. Symptoms typically include a burning pain followed by small blisters or sores. The first attack may also be accompanied by fever, sore throat, and enlarged lymph nodes. The rash usually heals within ten days, but the virus remains dormant in the trigeminal ganglion. The virus may periodically reactivate to create another outbreak of sores in the mouth or lip.

VZV globulin or VZV antibodies is an immune system medication that is used mostly for immunosuppressed patients who have been or may be exposed to the varicella zoster virus. It shortens the course of cutaneous disease and may protect against its dissemination. Varicella zoster virus is a human herpes virus that causes chickenpox, shingles, Ramsay Hunt syndrome type II, and postherpetic neuralgia. Unlike a Zoster vaccine which provides durable immunity, the protection is passive and short term; it may need to be readministered every 2-4 weeks as necessary. This medication is not recommended for administration to immune-competent persons for the treatment of active disease.

<span class="mw-page-title-main">Herpes simplex keratitis</span> Medical condition

Herpetic simplex keratitis is a form of keratitis caused by recurrent herpes simplex virus (HSV) infection in the cornea.

<span class="mw-page-title-main">Herpes zoster ophthalmicus</span> Shingles in the human eye

Herpes zoster ophthalmicus (HZO), also known as ophthalmic zoster, is shingles involving the eye or the surrounding area. Common signs include a rash of the forehead with swelling of the eyelid. There may also be eye pain and redness, inflammation of the conjunctiva, cornea or uvea, and sensitivity to light. Fever and tingling of the skin and allodynia near the eye may precede the rash. Complications may include visual impairment, increased pressure within the eye, chronic pain, and stroke.

<span class="mw-page-title-main">Carbocyclic nucleoside</span> Class of chemical compounds

Carbocyclic nucleosides are nucleoside analogues in which a methylene group has replaced the oxygen atom of the furanose ring. These analogues have the nucleobase attached at a simple alkyl carbon rather than being part of a hemiaminal ether linkage. As a result, they have increased chemical stability. They also have increased metabolic stability because they are unaffected by phosphorylases and hydrolases that cleave the glycosidic bond between the nucleobase and furanose ring of nucleosides. They retain many of the biological properties of the original nucleosides with respect to recognition by various enzymes and receptors.

HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.

References

  1. 1 2 3 4 5 6 7 8 9 Jasek W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 5246–8. ISBN   978-3-85200-181-4.
  2. "Brivudin (Zostex) besser als Aciclovir (Zovirax a.a.)?". Arznei-telegramm (in German). 5/2007.
  3. "UAW – Aus Fehlern lernen - Potenziell tödlich verlaufende Wechselwirkung zwischen Brivudin (Zostex) und 5-Fluoropyrimidinen" (PDF). Deutsches Ärzteblatt (in German). 103 (27). 7 July 2006.
  4. 1 2 Steinhilber D, Schubert-Zsilavecz M, Roth HJ (2005). Medizinische Chemie (in German). Stuttgart: Deutscher Apotheker Verlag. pp. 581–2. ISBN   3-7692-3483-9.
  5. Desgranges C, Razaka G, Rabaud M, Bricaud H, Balzarini J, De Clercq E (December 1983). "Phosphorolysis of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and other 5-substituted-2'-deoxyuridines by purified human thymidine phosphorylase and intact blood platelets". Biochemical Pharmacology. 32 (23): 3583–90. doi:10.1016/0006-2952(83)90307-6. PMID   6651877.
  6. Mutschler E, Schäfer-Korting M (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 847. ISBN   3-8047-1763-2.
  7. De Clercq E (December 2004). "Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster". Biochemical Pharmacology. 68 (12): 2301–15. doi:10.1016/j.bcp.2004.07.039. PMID   15548377.
  8. Tringali C, ed. (2012). Bioactive Compounds from Natural Sources (2nd ed.). CRC Press. p.  170.
  9. 1 2 International Drug Names : Brivudine.
  10. Wilhelmus KR (January 2015). "Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis". The Cochrane Database of Systematic Reviews. 1: CD002898. doi:10.1002/14651858.CD002898.pub5. PMC   4443501 . PMID   25879115.